Process for the preparation of vincamine

ABSTRACT

A new process for the preparation of vincamine and of homologues thereof containing acyl groups of 2 to 6 carbon atoms in the 14position, wherein 1-ethyl-2,3,4,6,7,12-hexahydroindolo(2,3a)quinolizine is reacted with an Alpha -acyloxy-acrylic acid derivative of the formula (R C1 5 alkyl) to obtain the corresponding 1-( Beta -acyloxyBeta -R-oxycarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7-hexahydro-12Hindolo(2,3 -a)quinolizine compound, this is converted by deacylation and reduction into the corresponding 1-( Beta hydroxy- Beta -R-oxycarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7,12,12boctahydroindolo(2,3 -a)quinolizine; the latter is treated with an oxidizing agent to yield a mixture of the desired vincamine derivative and the 14-epimer thereof. The latter can be epimerized in a known manner; by using silver carbonate as oxidizing agent, the epimerization occurs simultaneously.

United States Patent [191 Szantay et al.

[ Aug. 28, 1973 {73] Assignee: Richter Gedeon Vegyeszeti Gyar RT,

Budapest X, Hungary [22] Filed: May 2, 1972 [21] Appl. No.: 249,492

[30] Foreign Application Priority Data May 7, 1971 Hungary Rl-430 [52]US. Cl. 260/293.53, 260/295 A [51] Int. Cl....[. C07d 27/54 [58] Fieldof Search 260/293.53, 293.55

[56] References Cited UNITED STATES PATENTS 7/1969 Kuehne ..260/294.311/1970 Schut 260/295 5 7] ABSTRACT A new process for the preparation ofvincamine and of homologues thereof containing acyl groups of 2 to 6carbon atoms in the l4-position, wherein l-ethyl-2,3,4,6,7,l2-hexahydroindolo[2,3-a1quinolizine is reacted with ana-acyloxy-acrylic acid derivative of the formula (R CH, alkyl) to obtainthe corresponding l-(B-acyloxy-fl-R-oxycarbonyl-ethyl)-l-ethyl-1,2,3,4,6,7- hexahydro- 12l-i-indolo[ 2,3-a1quinolizine compound, this is converted bydeacylation and reduction into the corresponding1-(B-hydroxy-B-R-oxycarbonyl-ethyl)- l -ethyll ,2,3,4,6,7, 12,12b-octahydroindolo[2,3- alquinolizine; the latter is treated with anoxidizing agent to yield a mixture of the desired vincamine derivativeand the l4-epimer thereof. The latter can be epimerized in a knownmanner; by using silver carbonate as oxidizing agent, the epimerizationoccurs simultaneously.

6 Claims, No Drawings PROCESS FOR THE PREPARATION OF VINCAMINE Thisinvention relates to a process for the preparation of vincamine andrelated compounds having the general formula (1) wherein R represents aC...,, alkoxy group, or the R- CO-group represents a reactive groupwhich may be converted into an alkoxycarbonyl radical. Moreparticularly, this invention relates to the synthesis of vincamine andrelated compounds having the general formula (I) from novel intermediate-compounds. Also these novel intermediate compounds used as startingsubstances in the process of the invention possess biological activity,e.g. they have a vasodilatory effect.

It is known that (+)-vinca.mine occurring in nature is an importanttherapeutic agent, since it has sedative and antihypertensive effects[L.Szpomy, and K.Szasz: Arch. Exp. Path. Pharmac. 236 296(l959)]. It isalso known that the demands for (+)-Vincamine are so high that theycannot be satisfied by procedures based on the extraction of the plantVinca minor L.

Two syntheses have been described so far for the preparation of(+)-vincamine.

According to one of these known methods, a lactam ester prepared fromtriptamine and 4-ethyl-4-formyldimethyl-pimelate is reacted withphosphorous pentasulfide, thereafter the obtained thiolactam ester isdesulphurated, the formed amino ester is oxidized, finally it isconverted to (+)-vincarnine by treating it with an acid (US. Pat. No.3,454,583).

According to the second known method, the eightmembered ring of thecorresponding precursor compound is split in alkaline medium, theobtained compounds are reacted with diazomethane, and the formed hydroxyester is oxidized with a mixture of dimethylsulfoxide, triethylamine,pyridine-sulfur trioxide and water to yield (+)-vincamine [Chem. Comm.1490 (l- 969)].

The common disadvantage, however, of these syntheses is that they startfrom expensive, not easily available substances, moreover the methodsrequire complicated chromatographical separation and (+)-vincamine canbe obtained only with very low yields. A further disadvantage of theseknown processes is that they are not stereo-specific and the paperscited alone described only the preparation of racemic vincamine.

Utilizing the process of the invention, the above disadvantages can beovercome and vincamine can be prepared from easily available substanceswith excellent yield. By the proper selection of the reagents and thereaction conditions, an optically active product free of isomericderivatives (e.g. 1,4-epivincamine) can be obtained as end-product ofthe synthesis.

We have found that vincamine and related compounds of the generalformula (I) can be prepared in a very pure state, free of isomericby-products and with excellent yields, if the easily available l-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizine of the formula (II) ]J.Am. Chem. Soc. 87, 1580 (1965)] is used as starting material. Accordingto the process of the invention, vincamine and related compounds of thegeneral fonnula (I) are prepared by the following reaction steps:

a. l-Ethyl-2,3,4,6,7,l 2-hexahydroindolo[2,3-a]- quino-lizine of theformula (II) i Ii i s \/\N/\/ it i is reacted with an a-acyloxyacrylicacid derivative of the general formula (III) OAc wherein R and Ac havethe same meanings as stated above and X represents an inorganic anion,preferably perchlorate ionor the corresponding free base is b,. reducedand the obtained compound of the general formula (V) wherein R and Achave the same meanings as defined above or a salt thereof is reactedwith an deacylating agent to form a compound of the general formula(VII) (VII) wherein R has the same meanings as stated above bdeacylated, and the obtained compound of the general formula (VI) l is eN x k/\ I H E l 1 R-ii-oH-cml wherein R has the same meanings as statedabove s and epivincamine or a related compound of the general formula(VIII) is epimerized in a manner known per se,

C is reacted with silver carbonate to form vincamine or a relatedcompound of the general formula (I) wherein R has the same meanings asstated above and if necessary, the reactive group of a compound obtainedin any step of the synthesis is converted to an alkoxycarbonyl groupcontaining a C alkyl moiety, and if desired vincamine or the relatedcompound of the general fonnula (I) is resolved to yield thecorresponding optically active antipodes.

The process of the invention is preferably carried out as follows:

l-Ethyl-2,3,4,6,7, l 2-hexahydro-indolo[ 2,3- alquinolizine of theformula (II) is dissolved in an appropriate solvent, and ana-acyloxy-acrylic acid derivative of the general'formula (III) is addedto the solution. The reaction mixture is allowed to stand, thereafterthe solvent is distilled off in vacuo, and the compound of the generalformula (IV) is isolated from the residue in the form of a salt thereof,e.g. in the form of the corresponding perchlorate.

Thereafter the compound of the general formula (IV) which also possessbiological activity or the corresponding free base is reduced. Thisprocess is preferably carried out in methanol solution. As reducingagent, hydrogen is used in the presence of palladium catalyst. Thereaction is continued until the calculated amount of hydrogen isabsorbed. During this procedure a new compound of the general formula(V) is formed, which also possess biological activity. The compounds ofthe general formula (V) can also be prepared by reducing thecorresponding compounds of the general formula (IV) with a reducingagent other than hydrogen, e.g. with an alkali borohydride. If thereduction is carried out by catalytic hydrogenation or if an alkaliborohydride is used as reducing agent, a stereospecific reaction takesplace and compounds of the general formula (V), wherein the ethyl groupin position 1 and the hydrogen atom in position 12b on the D ring areeis configuration, are formed.

The obtained compound of the general formula (V) may be deacylated bydissolving the compound in an acidic solvent, preferably in methanolcontaining hydrochloric acid and boiling the solution. The separatedhydrochloric acid salt of the compound of the general formula VII) whichlatter also possess biological activity is filtered off, washed anddissolved in an appropriate solvent, preferably in aqueous acetone. Theobtained solution is rendered alkaline and the compound of the generalformula (Vll) is separated. The compound of the general formula (V) mayalso be treated with sodium methoxide in the presence of a solvent, e.g.in methanol to yield a compound of the general formula (VII).

The compounds of the general formula (Vll) may also be prepared asfollows: a compound of the general formula (IV), or the correspondingfree base is deacylated preferably with hydrochloric acid in methanoland the thus obtained compound of the general formula (VI), which alsopossesses biological activity, is reduced to a compound of the generalformula (VII). The reduction may be carried out as described at thepreparation of the compounds having the general formula (V). As reducingagent, e.g. an alkali borohydride or other reducing agents may be used,or the compounds of the general formula (VI) may be reduced withhydrogen in the presence of a catalyst. If the reduction is carried outby catalytic hydrogenation or if an alkali borohydride is used asreducing agent, a stereospecific reaction takes place.

The compounds of the general formula (VII) may be oxidized to a mixtureof vincamine and epivincamine or to a mixture of compounds of thegeneral formulae (1) and (VIII), respectively. The reaction ispreferably carried out as follows: a compound of the general formula(VII) is dissolved in an appropriate solvent, eg in dimethylsulfoxidmand a solution of phosphoric acid in dimethylsulfoxide is added to theformer solution. Thereafter freshly distilled dicyclohexyl carbodiimideis added dropwise to the reaction mixture, and the mixture is allowed tostand. After several hours of standing the mixture is poured onto ice,the solution is rendered alkaline, and the mixture is extracted with anappropriate solvent, preferably with dichloromethane. Thedichloro-methane solution is dried and the solvent is evaporated invacuo. The obtained residue is a mixture of (+)-vincamine and(+)-epivincamine or a mixture of compounds of the general formulae (I)and (VIII), respectively. The residue is crystallized from anappropriate solvent, preferably from a mixture of methanol and ether toyield (+)-vincamine or related compounds of the general formula (I).According to an other method the residue is not crystallized but it issubjected to epimerization as described in the British Patentapplication No. 3283/72 to yield (+)-vincamine or related compounds ofthe general formula (I).

According to another preferred method of the invention a compound of thegeneral formula (VII) is oxidized in benzene medium preferably withsilver carbonate. The reaction is carried out at the boiling point ofthe reaction mixture. The solvent is evaporated in vacuo to yield aresidue which is a mixture of (+)-vincamine and (+)-epivincamine or amixture of compounds of the general formulae (I) and (VIII),respectively. This mixture is worked up as described above.

According to a particularly preferred method of the invention theoxidation of the compounds of the general formula (VII) and thesubsequent epimerization of the products may be carried out in a singlestop. In this case the reaction is carried out with silver carbonate,but benzene is replaced by another inert solvent or solvent mixture. Assolvent, e.g. benzene-type hydrocarbons or their mixtures may be used. Aparticularly preferred solvent is xylene. The xylene solution isevaporated to about 20 percent of the original volume under reducedpressure. This operation is carried out under nitrogen atmosphere. Theresidual concentrate is allowed to stand, the separated crystals arefiltered off, washed and dried. In this way (+)-vincamine or relatedcompounds of the general formula (I) are obtained.

According to a method of the invention the C alkoxy group of thecompounds of the formulae (I), (IV), (V), (VII) or (VIII) is introducedinto the molecule after any of the synthesis steps by methods known perse.

(+)-Vincamine or related compounds having the general formula (I) may beresolved using 0,0- dibenzoyl tartaric acid, d-tartaric acid,d-camphorsulfonic acid or other optically active acids. The opticallyactive end-products may also be formed by resolving any of the racemicintermediates produced in the synthesis and carrying out the subsequentsteps with the optically active compounds. I

The invention is further elucidated by the aid. of th followingnon-limiting Examples.

EXAMPLE 1 PREPARATION OF (+)-VINCAMINE a. Preparation of1-(B-acetoxy-B-methoxycarbonylethyl)-l-ethyl-1,2,3,4,6,7-hexahydro-l2H-indolo[2,3-a]quinolizine perchlorate (Formula IV, R methoxy group, Ac acetyl group,X perchlorate ion) 7.09 g. (2.8 mmoles) of l-ethyl-2,3,4,6,7,l2-hexahydrol 2I-I-indolo[2,3-a1quinolizine (compound of the formula II)are dissolved in 100 ml. of dry dichloromethane. ml. ofa-acetoxy-acrylic acid methyl ester are added to the solution and thereaction mixture is allowed to stand at room temperature for 2 days.Dichloromethane is evaporated in vacuo, the dark, oily residue istriturated with 3X50 ml. of petroleum ether, dissolved in 20 ml. ofmethanol, and the solution is acidified to pH 5 with 70 percentperchloric acid. This latter operation is carried out with cooling. Theseparated l-(B-acetoxy-B-methoxy-carbonyl-ethyl l ethyl-1,2,3 ,4,6,7-hexahydro-l 2H-indolo[2,3- a]quinolizine perchlorate is filteredoff and washed with cold methanol and with ether. 7.00 g. of the productare obtained (yield 50 percent); m.p.: l52154 C.

Analysis:

Calculated for c u mmcl (496.93):

C=55.56% H=5.88% N=5.54%

Found: C 55.40 H 5.60 N 5.90

IR-spectrum: v 3,600 (OI-I), 3,500 (NH), 1,730 (CO,CH )m 1,760 (COOCH1,630, 1,538 (C N) cm.

b. Preparation of 1-(B-acetoxy-B-methoxycarbonylethyl)- l -ethyll,2,3,4,6,7 ,l 2,12b-octahydroindolo[2,3-a]quinolizine (Formula V, Rmethoxy group, Ac acetyl group) b,. 7.50 g. ofl-(B-acetoxy-B-methoxycarbonylethyl l -ethyl-l ,2,3,4,6,7-hexahydrol2I-I-indolo[2 ,3 a]quino-lizine perchlorate are dissolved in 350 ml. ofmethanol, and 4.5 g. of 10 percent palladium-oncarbon are added to thesolution. The reaction mixture is hydrogenated. The mixture absorbs thecalculated amount of hydrogen within about 2 hours. The mixture isfiltered and the filtrate is evaporated. 7 g. of 1(3-acetoxy-B-methoxycarbonyl-ethyl)-1-ethyll,2,3,4,6,7, l 2, l 2boctahydroindolo[2,3-a]qui-nolizine perchlorate are obtained, which maybe used in the next step without purification.

1 g. of l-(B-acetoxyfi-methoxycarbonyl-ethyl)-1- ethyl-l ,2,3,4,6,7,l2,1 Zb-octahydroindolol 2,3- a]quinolizine perchlorate are dissolved in5 ml. of 80 percent aqueous acetone, and the solution is alkalinizedwith ammonium hydroxide to pH 8. The separated crystallinel-(B-acetoxy-B-methoxycarbonylethyl )-l -ethyll ,2,3,4,6,7, l 2,12b-octahydroindolo[2,3-a1quinolizine melts at 144 C after recrystal-Calculated for c,,a,,u,o, (398.49):

C=69.32% H=7.58% N=7.03

Found: C 69.58 H 7.77 N 7.06

IR-spectrum: v, 3,410 (NH), 1,720 co cn 1,760 (OCOCH cm.

b 1 g. of l-(B-acetoxy-B-methoxycarbonyl-ethyl)-lethyl-1 ,2,3,4,6,7-hexahydro- 12H-indolo[2,3- a]quinolizine perchlorate aresuspended in ml. of methanol, and 0.7 g. of sodium borohydride are addedto the suspension under cooling in ice water. During the addition thereaction mixture is vigorously stirred. After 10 minutes the mixture isacidified to pH 6 with glacial acetic acid, and the mixture isevaporated to dryness in vacuo. The residue is partitioned between 5percent aqueous sodium hydrocarbonate solution and ether. The ethereallayer is dried and evaporated to dryness. The residue is recrystallizedfrom methanol. In this way 0.5 g. ofl-(fi-acetoxy-B,-methoxycarbonylethyl)-l-ethyl-l,2,-3,4,6,7,l2,12b-octahydroindolol 2,3-a1quinolizine are obtained.

c. Preparation of l-(B-hydroxy-B-methoxycarbonylethyl)- l -ethyl-l,2,3,4,6,7-hexahydro-l 2H-indolo[ 2,3- a]quinolizine perchlorate(Formula VI, methoxy group, X perchlorate ion) 0.3 g. of1-(B-acetoxy-B-methoxycarbonyl-ethyl)-1- ethyl-l,2,3,4,6,7-hexahydro-12H-indo1o[2,3- a]quinolizine perchlorate(preparedas described in paragraph (a.) are dissolved in 10 ml. of methanolcontaining 0.165 g. of hydrochloric acid per ml. The solution is boiledfor 2 hours, thereafter it is evaporated to dryness. The residue isdissolved in water and 70 percent aqueous perchloric acid is added tothe solution. 0.2 g. of l-(B-hydroxy-B-methoxycarbonyl-ethyl)-1- ethyl-l,2,3 ,4,6,7-hexahydro-12H-indolo[2,3-a}quinolizine-perchlorate areobtained; m.p.: l80l81 C.

Analysis: Calculated for C H ,N O-,Cl (454.90):

C=55.44% H=5.81% N=6.15 Found: C 55.49 H 5.98 6.08

IR spectrum: 11 3,450 (NH), 3,360 (OI-I), 1,718 (COOCI-l 1,620, 1,535(C=N), 1,442, 1,100 cm.

d. Preparation of 1-(B-hydroxy-B-methoxycarbonylethyl 1 -ethyl-l,2,3,4,6,7, l 2,12H-octahydroindolo[2,3-a]quinolizine (Formula VII, Rmethoxy group) d 7 g. of 1-(fi-acetoxy-B-methoxycarbonyl-ethyl)-I-ethyl-1,2,3 ,4,6,7, 1 2, 12b-octahydroindolo[2,3- a]quinolizineperchlorate are dissolved in 150 ml. of methanol containing 0.165 g. ofhydrochloric acid per ml., and the solution is refluxed for 2 hours.Thereafter the solution is evaporated in vacuo to 30 ml. The separatedsalt is filtered off and washed with cold methanol and ether. Theobtained 5.5 g. of the salt are dissolved in a mixture of 80 ml. ofacetone and 80 ml. of water, and the solution is alkalinized withpercent aqueous sodium carbonate solution. The separated white,crystalline 1 -(B-hydroxy-B-methoxy-carbonyl-ethyl)- I ethyll ,2,3,4,6,7,12,12b-octahydroindolo[2,3- a]quinolizine is separated byfiltration and washed with water. 4.3 g. (80 percent) of the desiredproduct are obtained; m.p.: 234 C.

Analysis: Calculated for C H N O (356.45):

C=70.75% l-I=7.91% N=7.86%

Found: C 70.47 H 7.92 N 8.14

IR-spectrum: 11 3,420 (OH, NH), 1,742 (CO CH- 1,200, 1,130, 745 cm".

d 1 g. of 1-(B-acetoxy-B-methoxycarbonyl-ethyl)-lethyl-l,2,3,4,6,7,12,12b-octahydroindolo[2,3- a]quino-lizine perchlorate areadded with 30 ml. of methanolic sodium methoxide solution (containing0.18 g. of sodium per 100 ml. of methanol), and the mixture is boiledfor 40 minutes. The sodium methoxide is decomposed with glacial aceticacid and the solution is evaporated to dryness in vacuo. The residue issuspended in 5 percent aqueous sodium hydrocarbonate solution, and thesuspension is extracted with dichloromethane. The dichloromethanesolution is dried over magnesium sulfate and the solvent is evaporated.

e,. 1.00 g. (2.8 mmoles) ofl-(B-hydroxy-B-methoxycarbonyl-ethyl)-l-ethyl-l,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine are dissolved in amixture of 13 ml. of dry dimethyl sulfoxide and 4 ml. of a 1 m. solutionof phosphoric acid in dimethylsulfoxide. When the total amount of thesolid entered into solution, the solution is added with 1.66 g. offreshly distilled dicyclohexyl carbodiimide, and the reaction mixture isal lowed to stand at room temperature for 7 hours. Thereafter themixture is poured into 130 ml. of ice water, the mixture is renderedalkaline with 5 percent aqueous sodium carbonate solution, finally it isextracted with dichloromethane. The dichloromethane solutions arecombined, dried over magnesium sulphate, and the solvent is evaporatedin vacuo. 0.25 g. of residue are obtained. The residue is a mixture of(+)-vincamine and (+)-epi-vincamine.

The residue is recrystallized from a 1:1:] mixture of dichloromethane,methanol and diethyl ether. 0.095 g. of (+)-vincamine are obtained;m.p.: 224-225 C.

The mother liquor obtained in the above process is evaporated to yield0.098 g. of a mixture of epivincamine and vincamine. This mixture isrecrystallized from methanol to yield 0.072 g. of pure (+)-epivincamine.M.p.: 210 C.

IR spectrum: 1 1,756 (CO CH 1,462, 1,370, 1- ,330, 1,310, 1,258, 1,240,1,200, 1,188, 1,088, 1,060, 1,020, 810, 756 cm.

c 0.1 g. of l-(B-hydroxy-B-methoxycarbonyl-ethy])-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a1quinolizine aredissolved in 10 ml. of benzene. 1.5 g. of silver carbonate celitereagent (containing 50 percent of silver carbonate) are added, and themixture is boiled for 48 hours. The mixture if filtered, the benzenefiltrate is evaporated in vacuo. The 0.095 g. of residue is a mixture of(+)-vincamine and (+)-epivincamine. The mixture is subjected tofractional crystallization (solvent: 1:1 mixture of dichloromethane andmethanol) to yield 0.015 g. of -epivincamine.

f. Preparation of (+)-vincamine (Formula I, R methoxy group) f 1 g. of amixture of (+)-vincamine and (+)-epivincamine (prepared as described inparagraph c) are dissolved in ml. of xylene and 7.5 g. of silvercarbonate celite reagent (containing 50 percent of silver carbonate) areadded to the solution. The reaction mixture is boiled for about 3 to 4hours. The conversion is monitored by thin layer chromatography. At theend of the boiling the mixture is filtered, the filter cake is washedwith hot xylene, the xylene solutions are combined and evaporated invacuo to about 20 percent of the original volume. This operation iscarried out under a nitrogen atmosphere. The concentrate is left tostand for 1 day. Next day the separated crystals are filtered off,washed and dried. 0.8 g. of (+)-vincamine are obtained; m.p.: 227-228 C.

f 2.0 g. of 1-(B-hydroxy-B-methoxycarbonyl-ethyl)1,2,3,4,6,7,l2,12b-octahydroindolo[2 ,3-a]qui-nolizine (prepared asdescribed in paragraph d) are dissolved in 100 ml. of xylene, thesolution is heated to boiling; and 10.0 g. of silvercarbonate celitereagent (containing 50 percent of silver carbonate) are added to the hotsolution with constant stirring. The reaction mixture is boiled for 5hours. The progress of the conversion is monitored by thin layerchromatography. Thereafter the xylene mixture is filtered hot, thefiltrate is cooled on a mixture of salt and ice, and after several hoursthe separated crystalline (+)-vincamine is filtered off. Yield: 1.44 g.(75 M.p.: 225 C.

The xylene mother liquor is evaporated to one-third of its originalvolume and the concentrate is cooled. A further 0.16 g. of crystallinesubstance is obtained (total yield: 80 this second crop may be, however,a mixture of (+)-vincamine and (+)-epivincamine. This latter fraction iseither recrystallized or used in the former oxidation step as startingsubstance.

g. Preparation of (+)-vincamine g 0.3 g. of (+)-vincamine and 0.3 g. of0.0- dibenzoyl tartaric acid are dissolved in 6 ml. of hot methanol. Ifnecessary, the mixture is filtered hot. The solution is allowed to cooland seeded with a crystal of (+)-vincamine 0,0'-dibenzoyl tartrate(m.p.: 205 C). The mixture is allowed to stand at room temperature fortwo days, thereafter the separated crystals are collected by filtrationand washed with cold methanol. Yield: 0.15 g. (50 percent). M.p.: 205 C.

The thus-obtained salt is treated with 5 percent aqueous sodiumcarbonate solution. The free base is extracted with dichloromethane. Thedichloromethane solution is dried and evaporated. 0.08 g. of(+)-vincamine are obtained, m.p.: 228 C (11),, +4l.32 (c l, pyridine).

g The process described in paragraph g is repeated with the differencethat d-tartaric acid is used as resolving agent. (+)-Vincamine tartratemelts at 218 C. The yield and the optical purity grade of (+)-vincamineobtained in this process is the same as given in paragraph 1- g;,. Theprocess described in paragraph g is repeated with the difference thatd-camphorsulfanic acid is used as resolving agent. (+)-Vincamined-camphorsulfonate melts at 130 C (the substance crystallizes withmethanol). The yield and the optical purity grade of (+)-vincamineobtained in this process is the same as given in paragraph g,.

EXAMPLE 2 The ethyl analogue of (+)-vincamine (Formula I, R ethoxygroup) The process described in Example 1 is repeated with thedifference that a-acetoxy-acrylic acid methyl ester is replaced bya-acetoxy-acrylic acid ethyl ester.

The ethyl-analogue of -(+)-vincamine (Formula 1, R ethoxy group), meltsat 245 C. (01),, 64.1 (c 1, pyridine).

EXAMPLE 3 Preparation of1-(fl-hydroxy-B-methoxycarbonylethyl)-l-ethyl-1,2,3,4,6,7-hexahydro-lZH-indolo[2,3- a]qui-nolizine perchlorate (Formula Vl, R methoxy group, Xperchlorate ion) The process described in Example 1, paragraph a. isrepeated with the difference that a-acetoxy-acrylic acid methyl ester isreplaced by a-acetoxyacrylonitrile. The oily residue obtained after theevaporation of dichloromethane is purified through the perchlorate salt.The purified substance is boiled in methanol containing hydrochloricacid until the nitrile and amide bands disappear in the infraredspectrum of the mixture. Thereafter the solution is worked up asdescribed in Example 1, paragraph c.l-(B-Hydroxy-fimethoxycarbonyl-ethyl)-1-ethyl-1 ,2,3,4,6,7-hexahydro-l2H-indolo [2,3-a]quinlizine perchlorate is obtained.The product is identical with the compound obtained in Example 1,paragraph c.

What we claim is: 1. A process for the preparation of compounds of the 5formula I N -\l; no i i l |1i w li E a m wherein represents analkoxycarbonyl radical of 2 to 6 carbon atoms or a reactive groupconvertible into the said alkoxycarbonyl radical, characterized in thata. l-ethyl-2,3,4,6,7, l 2-hexahydroindolo[ 2,3-

a]quino1izine of the formula II l is x l I ll.'r*

is reacted with an a-acyloxy-acrylic acid derivative of the formula ll]A- III 40 0 c wherein R has the same meanings as above the Ac representsan acyl radical b. the obtained compound of the general formula IVwherein R and Ac have the same meanings as above, or a salt thereof isreacted with a deacylating agent to form a compound of the generalformula VII wherein R has the same meanings as stated above,

(1. the obtained compound of the general formula VII is treated with anoxidizing agent to yield a mixture of compounds of the formulae I andVIII 0 ll (v1 I n wherein R has the same meanings as stated above, andthe compound of the formula VIII is epimerized in a manner known per seinto a compound of the formula I. v

2. A process for the preparation of compounds of the formula I wherein ICgHg is reacted with an a-acyloxy-acrylic acid derivative of the formualIII um (III) wherein R has the same meanings as above and Ac representsan acyl radical,

b. the obtained compound of the general formula IV wherein R and Ac havethe same meanings as above and X represents an inorganic anion, or thecorresponding free base is deacylated,

c. the obtained compound of the general formula VI u I I wherein R and Xhave the same meanings as defined above, is reduced to form a compoundof the general wherein R has the meanings as stated above,

d. the obtained compound of the general formula VII is treated with anoxidizing agent to yield a mixture of compounds of the formulae I andVIII wherein R has the same meanings as stated above, and the compoundof the formual is epimerized in a manner known per se into a compound ofthe formula I.

3. A process as claimed in claim 1, wherein the compound of the formulaVII is oxidized with silver carbonate, whereby the formed epimer of theformula VIII is simultaneously epimerized, to yield a compound of theformula I.

4. A process as claimed in claim 2, wherein the compound of the formulaVII is oxidized with silver carbonate, whereby the formed epimer of theformula VIII is simultaneously epimerized, to yield a compound of theformula I.

5. A process for the preparation of vincamine, whereis used as reactionmedium.

salt

2. A process for the preparation of compounds of the formula I
 3. Aprocess as claimed in claim 1, wherein the compound of the formula VIIis oxidized with silver carbonate, whereby the formed epimer of theformula VIII is simultaneously epimerized, to yield a compound of theformula I.
 4. A process as claimed in claim 2, wherein the compound ofthe formula VII is oxidized with silver carbonate, whereby the formedepimer of the formula VIII is simultaneously epimerized, to yield acompound of the formula I.
 5. A process for the preparation ofvincamine, wherein1-ethyl-2,3,4,6,7,12-hexahydro-12H-indolo(2,3-a)-quinolizine is reactedwith Alpha -acetoxy-acrylic acid methyl ester, the obtained 1-( Beta-acetoxy- Beta-methoxycarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolizine or a salt thereof is reduced and deacylated to yield 1-(Beta -hydroxy- Beta-methoxycarbonyl-ethyl)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo(2,3-a)quinolizin, this product or a salt thereof is treated with anoxidizing agent.
 6. A process as claimed in claim 5, wherein silvercarbonate is used as oxidizing agent and toluene or xylene is used asreaction medium.